The application of modern technologies to the biology of the normal, dysplastic, and malignant respiratory epithelium promises to allow better prediction of clinical behavior as well as to provide intermediate endpoint biomarkers for therapeutic trials. Major obstacles to the use of molecular genetics in the respiratory epithelium include the difficulty in identifying high-risk individuals for study and the inability to identify dysplastic epithelium for biopsy and the small amount of tissue available. As a result, virtually all studies of the biology of premalignant respiratory epithelium have either utilized screening methods, such as sputum cytology, or epithelial harvest of dysplastic areas in surgical resection specimens from individuals with lung cancer. The former has the disadvantage that limited analysis is possible and the latter approach likely biases analysis toward the examination of more advanced dysplasias which have already demonstrated the potential to progress to carcinoma. During the initial funding period of the University of Colorado SPORE in Lung Cancer, many of the difficulties involved in studying premalignant biology have been addressed through the validation of an appropriate high- risk population for initial screening, the use of fluorescence bronchoscopy for identification of dysplastic epithelium for biopsy, the development of methods for genetic analysis of respiratory epithelium, and the collaboration of several groups of basic scientists with interests in various aspects of the progression to lung cancer. The following hypotheses will now be tested through their respective specific aims with the goal of developing improved methods of early detection and novel approaches to prevention. 1. Fluorescence bronchoscopy improves detection of premalignant dysplasias over white-light bronchoscopy. 2. Exposure to tobacco smoke and other carcinogens modifies the expression of molecular and phenotypic markers in airway epithelium, with more extensive alterations occurring in histologically advanced dysplasias. 3. Dysplastic airway epithelium reverts toward normal with therapeutic intervention, including smoking cessation, chemoprevention, and chemotherapy and/or radiotherapy. 4. Biomarkers identified in premalignant dysplasias and lung tumors have prognostic significance. Each of these hypotheses will be tested through the development and implementation of clinical trial protocols. These studies will allow improvements in definition of high-risk individuals and populations, as well as provide intermediate endpoint biomarkers to accelerate the evaluation of therapeutic interventions.